The present invention relates to novel oxo azabicyclic compounds which are useful for preparing medicinal products for treating complaints involving a therapy with a matrix metalloprotease-13 (MMP-13) inhibitor. These medicinal products are useful in particular for treating certain inflammatory conditions such as rheumatoid arthritis or osteoarthritis, as well as certain proliferative conditions such as cancers, particularly human breast cancer.
Matrix metalloproteases (MMPs) are enzymes which are involved in the renewal of extracellular matrix tissue, such as cartilage, tendons and joints. MMPs bring about the destruction of the extracellular matrix tissue, which is compensated for, in a non-pathological physiological state, by its simultaneous regeneration.
Under normal physiological conditions, the activity of these extremely aggressive peptidases is controlled by specialized proteins which inhibit MMPs, such as the tissue inhibitors of metalloprotease (TIMPs).
Local equilibrium of the activities of MMPs and of TIMPs is critical for the renewal of the extracellular matrix. Modifications of this equilibrium which result in an excess of active MMPs, relative to their inhibitor, induce a pathological destruction of cartilage, which is observed in particular in rheumatoid arthritis and in osteoarthritis.
In pathological situations, an irreversible degradation of articular cartilage takes place, as is the case in rheumatic diseases such as rheumatoid arthritis or osteoarthritis. In these pathologies, the cartilage degradation process predominates, leading to a destruction of the tissue and resulting in a loss of function.
At least twenty different matrix metalloproteases have been identified to date and are subdivided into four groups, the collagenases, the gelatinases, the stromelysins and the membrane-type MMPs (MT-MMPs), respectively.
Matrix metalloprotease-13 (MMP-13) is a collagenase-type MMP which constitutes the predominant collagenase observed during osteoarthritis, in the course of which pathology the chondrocyte directs the destruction of cartilage.
There is a need for novel MMP inhibitors, more particularly for MMP-13 inhibitors, in order to prevent and/or correct the imbalance in the renewal of extracellular matrix tissue, such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPD), age-related macular degeneration (ARMD) and cancer.
MMP-inhibitor compounds are known. Most of these MMP-inhibitors are not selective for a single MMP, such as those described by Montana and Baxter (2000) or by Clark et al. (2000).
There is also a need in the prior art for novel inhibitors that are active on matrix metalloprotease-13, in order to enrich the therapeutic arsenal that can be used for treating pathologies associated with the destruction of the extracellular matrix and with cancer.
The patent application WO9826664 describes quinazolinone compounds which are used as new antifungic compounds.
The compounds of the present application are novel and represent powerful inhibitors of MMP-13. They are consequently of use in the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases (COPDs), age-related degeneration (ARNMD) and cancer.
The applicant has identified novel oxo azabicyclic compounds that are matrix metalloprotease inhibitors, and more specifically compounds that are selective MMP-13 inhibitors.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
X1, X2, and X3, independently of each other, represent a nitrogen atom or a group xe2x80x94CR3 in which R3 represents a group selected from hydrogen, (C1-C6)alkyl, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, and halogen, with the proviso that not more than two of the groups X1, X2 and X3 simultaneously represent a nitrogen atom,
G1 represents a group selected from those of formulae (i/a) and (i/b): 
xe2x80x83in which:
the carbon atom with number 2 is attached to the group Nxe2x80x94R1 in the ring,
R4 and R5, identical or different, independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, cycloalkyl, cycloalkyl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, heterocycloalkyl, and heterocycloalkyl(C1-C6)alkyl,
R6 represents a group selected from:
hydrogen, trifluoromethyl, OR7, NR7R8, in which R7 and R8, identical or different independently of each other, represent hydrogen or (C1-C6)alkyl,
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, cycloalkyl(C1-C6)alkyl, heteroaryl, heteroaryl(C1-C6)alkyl, heterocycloalkyl, and heterocycloalkyl(C1-C6)alkyl, these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from halogen, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, each alkyl moiety being identical or different independently of each other, cyano, trihalogeno(C1-C6)alkyl, (C1-C6)acyl, xe2x80x94C(xe2x95x90O)OR7, xe2x80x94OR7 and xe2x80x94SR7, in which R7 is as defined hereinbefore,
G2 represents a group selected from carbon-carbon triple bond, xe2x80x94CHxe2x95x90Cxe2x95x90CHxe2x80x94, Cxe2x95x90O, Cxe2x95x90S, S(O)n1 in which n1 represents an integer from 0 to 2 inclusive, and a group of formula (i/c): 
in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Y1 represents a group selected from oxygen, sulphur, xe2x80x94NH and xe2x80x94N(C1-C6)alkyl, and Y2 represents a group selected from oxygen, sulphur, xe2x80x94NH and xe2x80x94N(C1-C6)alkyl,
n represents an integer from 0 to 6 inclusive,
Z1 represents xe2x80x94CR9R10, wherein R9, and R10, identical or different independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, trihalogeno(C1-C6)alkyl, halogen, xe2x80x94OR7, xe2x80x94SR7, and xe2x80x94C(xe2x95x90O)OR7, in which R7 is as defined hereinbefore, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino in which each alkyl moiety is identical or different independently of each other, and
wherein when n is greater than or equal to 2, the hydrocarbon chain Z1 optionally contains one to two isolated or conjugated multiple bonds,
and/or wherein when n is greater than or equal to 2, one of said xe2x80x94CR9R10 may optionally be replaced with a group selected from oxygen, S(O)n1 in which n1 is as defined hereinbefore, xe2x80x94NH and xe2x80x94N(C1-C6)alkyl,
A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or 6-membered monocycle,
R1 represents a group selected from:
hydrogen,
(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, these groups may be optionally substituted with one or more groups, which may be identical or different independently of each other, selected from amino, cyano, trihalogeno(C1-C6)alkyl, cycloalkyl, xe2x80x94C(xe2x95x90O)NR7R8, xe2x80x94C(xe2x95x90O)OR8, OR8, SR8, in which R7 and R8, which may be identical or different independently of each other, represent hydrogen or (C1-C6)alkyl,
and the group of formula (i/d): 
in which p is an integer from 0 to 8 inclusive,
Z2 represents xe2x80x94CR11R12 wherein R11 and R12, identical or different independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, phenyl, trihalogeno(C1-C6)alkyl, halogen, amino, OR7, SR7 and xe2x80x94C(xe2x95x90O)OR7 in which R7 represents hydrogen or (C1-C6)alkyl, and
wherein when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or two isolated or conjugated multiple bonds,
and/or wherein n is greater than or equal to 2, one of said xe2x80x94CR11R12 may optionally be replaced with a group selected from oxygen, S(O)n1 in which n1 is as defined hereinbefore, xe2x80x94NH, xe2x80x94N(C1-C6)alkyl, and carbonyl,
B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or 6-membered monocycle,
q is an integer from 0 to 7 inclusive,
the group(s) G3, which may be identical or different independently of each other, is (are) selected from (C1-C6)alkyl, halogen, CN, NO2, CF3, OCF3, xe2x80x94(CH2)kNR13R14, xe2x80x94N(R13)C(xe2x95x90O)R14, xe2x80x94N(R13)C(xe2x95x90O)OR14, xe2x80x94N(R13)SO2R14, xe2x80x94N(SO2R13)2, xe2x80x94OR13, xe2x80x94S(O)k1R13, xe2x80x94SO2xe2x80x94N(R13)xe2x80x94(CH2)k2xe2x80x94NR14R15, xe2x80x94(CH2)kSO2NR13R14, xe2x80x94X4(CH2)kC(xe2x95x90O)OR13, xe2x80x94(CH2)kC(xe2x95x90O)OR13, xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)k2xe2x80x94NR13R14, xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)k2xe2x80x94C(xe2x95x90O)OR16, xe2x80x94X4(CH2)kC(xe2x95x90O)NR13R14, xe2x80x94(CH2)kC(xe2x95x90O)NR13R14, xe2x80x94R17xe2x80x94C(xe2x95x90O)OR13, xe2x80x94X5xe2x80x94R18, and xe2x80x94C(xe2x95x90O)xe2x80x94R19xe2x80x94NR13R14 in which:
X4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (C1-C6)alkyl group,
k is an integer from 0 to 3 inclusive,
k1 is an integer from 0 to 2 inclusive,
k2 is an integer from 1 to 4 inclusive,
R13, R14 and R15, which may be identical or different independently of each other, are selected from hydrogen and (C1-C6)alkyl,
R16 represents a group selected from (C1-C6)alkyl, xe2x80x94R19xe2x80x94NR13R14, xe2x80x94R19xe2x80x94NR13xe2x80x94C(xe2x95x90O)xe2x80x94R19xe2x80x94NR14R15, and xe2x80x94C(xe2x95x90O)Oxe2x80x94R19xe2x80x94NR13R14 in which R19 represents a linear or branched (C1-C6)alkylene group, and R13, R14 and R15 are as defined hereinbefore,
R17 represents a (C3-C6)cycloalkyl group,
X5 represents a group selected from single bond, xe2x80x94CH2xe2x80x94, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C1-C6)alkyl group,
R18 represents a group selected from:
5- or 6-membered monocycle aryl, heteroaryl, which is optionally substituted by one or more groups, which may be identical or different, selected from (C1-C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and xe2x80x94C(xe2x95x90O)OR7 wherein R7 represents hydrogen or (C1-C6)alkyl,
and 5- or 6-membered monocycle cycloalkyl, heterocycloalkyl, which is optionally substituted by one or more groups, which may be identical or different, selected from (C1-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and xe2x80x94C(xe2x95x90O)OR7 wherein R7 represents hydrogen or (C1-C6)alkyl,
m is an integer from 0 to 7 inclusive,
the group(s) R2, which may be identical or different independently of each other, is (are) selected from (C1-C6)alkyl, halogen, xe2x80x94CN, NO2, SCF3, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NR7R8, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94SOR8, xe2x80x94SO2R8, xe2x80x94(CH2)kSO2NR7R8, xe2x80x94X7(CH2)kC(xe2x95x90O)OR8, xe2x80x94(CH2)kC(xe2x95x90O)OR8, xe2x80x94X7(CH2)kC(xe2x95x90O)NR7R8, xe2x80x94(CH2)kC(xe2x95x90O)NR7R8, and xe2x80x94X8xe2x80x94R20 in which:
X7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (C1-C6)alkyl,
k is an integer from 0 to 3 inclusive,
R7 and R8, which may be identical or different independently of each other, are selected from hydrogen and (C1-C6)alkyl,
X8 represents a group selected from single bond, xe2x80x94CH2xe2x80x94, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C1-C6)alkyl group,
R20 represents 5- or 6-membered monocycle aryl, heteroaryl, cycloalkyl, or heterocycloalkyl which is optionally substituted by one or more groups, which may be identical or different, selected from (C1-C6)alkyl, halogen, hydroxy and amino, and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur,
optionally, the racemic forms thereof, isomers thereof, N-oxides thereof, and the pharmaceutically acceptable salts thereof.
According to a first embodiment, the invention relates to compounds of formula (I) wherein:
G2 represents a group selected from Cxe2x95x90O, Cxe2x95x90S, S(O)n1 in which n1 represents an integer from 0 to 2 inclusive, or a group of formula (i/c): 
in which the carbon atom with number 1 is attached to the bicycle of the compound of formula (I), Y1 represents a group selected from oxygen, sulphur, xe2x80x94NH and xe2x80x94N(C1-C6)alkyl, and Y2 represents a group selected from oxygen, sulphur, xe2x80x94NH and xe2x80x94N(C1-C6)alkyl,
X1, X2, X3, G1, n, Z1, A, R1, m and R2 are as defined in formula (I).
According to a second embodiment, the invention relates to compounds of formula (1) wherein:
G2 represents a carbon-carbon triple bond,
n represents an integer from 1 to 6 inclusive,
X1, X2, X3, G1, Z1, A, R1, m and R2 are as defined hereinbefore.
According to a third embodiment, the invention relates to compounds of formula (I) wherein:
G2 represents a carbon-carbon triple bond,
n is zero,
Z1 is absent,
A represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or 6-membered monocycle,
X1, X2, X3, G1, R1, m and R2 are as defined hereinbefore.
According to a fourth embodiment, the invention relates to compounds of formula (I) wherein:
G2 represents a carbon-carbon triple bond,
n is zero,
Z1 is absent,
A represents a phenyl group,
R1 represents a hydrogen atom or a group of formula (i/d): 
in which p is an integer from 0 to 8 inclusive,
Z2 represents xe2x80x94CR11R12 wherein R11 and R12, identical or different independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, phenyl, trihalogeno(C1-C6)alkyl, halogen, amino, OR7, SR7 and xe2x80x94C(xe2x95x90O)OR7 in which R7 represents hydrogen or (C1-C6)alkyl, and
wherein when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or two isolated or conjugated multiple bonds,
and/or wherein n is greater than or equal to 2, one of said xe2x80x94CR11R12 may optionally be replaced with a group selected from oxygen, S(O)n1 in which n1 is as defined hereinbefore, xe2x80x94NH, xe2x80x94N(C1-C6)alkyl, and carbonyl,
B represents a phenyl group,
q is an integer from 1 to 7 inclusive,
the group(s) G3, which may be identical or different independently of each other, is (are) selected from xe2x80x94(CH2)kNR13R14, xe2x80x94N(R13)C(xe2x95x90O)OR14, xe2x80x94N(R13)SO2R14, xe2x80x94N(SO2R13)2, xe2x80x94S(O)k1R13, xe2x80x94SO2xe2x80x94N(R13)xe2x80x94(CH2)k2xe2x80x94NR14R15, xe2x80x94(CH2)kSO2NR13R14, xe2x80x94X4(CH2)kC(xe2x95x90O)OR13, xe2x80x94(CH2)kC(xe2x95x90O)OR13, xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)k2xe2x80x94NR13R14, xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)k2xe2x80x94C(xe2x95x90O)OR16, xe2x80x94X4(CH2)kC(xe2x95x90O)NR13R14, xe2x80x94(CH2)kC(xe2x95x90O)NR13R14, xe2x80x94R17xe2x80x94C(xe2x95x90O)OR13, xe2x80x94X5xe2x80x94R18, xe2x80x94C(xe2x95x90O)xe2x80x94R19xe2x80x94NR13R14 and xe2x80x94X6xe2x80x94R21 in which:
X4 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (C1-C6)alkyl group,
k is an integer from 0 to 3 inclusive,
k1 is an integer from 1 to 2 inclusive,
k2 is an integer from 1 to 4 inclusive,
R13, R14 and R15, which may be identical or different independently of each other, are selected from hydrogen and (C1-C6)alkyl,
R16 represents a group selected from (C1-C6)alkyl, xe2x80x94R19xe2x80x94NR13R14, xe2x80x94R19xe2x80x94NR13xe2x80x94C(xe2x95x90O)xe2x80x94R19xe2x80x94NR14R15, and xe2x80x94C(xe2x95x90O)Oxe2x80x94R19xe2x80x94NR13R14 in which R19 represents a linear or branched (C1-C6)alkylene group, and R13, R14 and R15 are as defined hereinbefore,
R17 represents a (C3-C6)cycloalkyl group,
X5 represents a group selected from single bond, xe2x80x94CH2xe2x80x94, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C1-C6)alkyl group,
R18 represents a group selected from heteroaryl, cycloalkyl, heterocycloalkyl, these groups being 5- or 6-membered monocycle or bicycle composed of two 5- or 6-membered monocycle, which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (C1-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and xe2x80x94C(xe2x95x90O)OR7 wherein R7 represents hydrogen or (C1-C6)alkyl,
X6 represents a group selected from xe2x80x94CH2xe2x80x94, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C1-C6)alkyl group,
R21 represents a phenyl group which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (C1-C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and xe2x80x94C(xe2x95x90O)OR7 wherein R7 represents hydrogen or (C1-C6)alkyl,
and X1, X2, X3, G1, m and R2 are as defined in formula (I).
The substituent R1 that is preferred according to the invention is the group of formula (i/d): 
wherein Z2, p, B, G3 and q are as defined in the compound of formula (I).
More particularly, the substituent R1 that is preferred according to the invention is the group of formula (i/d): 
wherein Z2 represents a group xe2x80x94CR11R12 in which R11 and R12 represents each a hydrogen atom., and p, B, G3 and q are as defined in the compound of formula (I).
More particularly, the substituent R1 that is preferred according to the invention is the group of formula (i/d): 
wherein p is one, and Z2, B, G3 and q are as defined in the compound of formula (I).
More particularly, the substituent R1 that is preferred according to the invention is the group of formula (i/d): 
wherein B represents a phenyl group, q is equal to 0 or 1, and G3, when it is present, represents a group selected from OR13, halogen, S(O)k1R13 and (CH2)kC(xe2x95x90O)OR13 in which R13 represents an hydrogen atom or a (C1-C6)alkyl group, k is zero, and k1 is two, and Z2, p are as defined in the compound of formula (I).
The invention relates also to the compounds of formula (I) wherein G1 represents a group of formula (i/a) in which R4 represents a hydrogen atom or a methyl group, or a group of formula (i/b) in which R4 and R5, identical, represent each a hydrogen atom or a methyl group, and R6 represents a hydrogen atom or a methyl group, and X1, X2, X3, G2, Z1, n, m and R2 are as defined in formula (I).
Preferred compounds of the invention are compounds of formula (I) wherein X1 represents a group xe2x80x94CR3 in which R3 represents a hydrogen atom, X2 represents a nitrogen atom or a group xe2x80x94CR3 in which R3 represents a hydrogen atom, and X3 represents a group xe2x80x94CR3 in which R3 represents a hydrogen atom.
Other preferred compounds of the invention are compounds wherein G2 represents a carbon-carbon triple bond or a group of formula (i/c) in which Y1 represents an oxygen atom, and Y2 represents a group xe2x80x94NH.
Still more preferred compounds of the invention are those compounds of formula (I) wherein Z1 represents xe2x80x94CR9R10 in which R9 and R10 represent each a hydrogen atom, and n is one.
Especially preferred compounds of the invention are compounds wherein A represents a group selected from phenyl and pyridyl, m is zero or one, and R2 represents a (C1-C6)alkoxy group or a hydrogen atom.
More particularly, the invention relates to the following compounds of formula (I):
3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
3-(4-methoxy-benzyl)-2-methyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide, hydrochloride
3-(4-methoxy-benzyl)-1-methyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
3-(4-methoxy-benzyl)-1,2,2-trimethyl-4-oxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
4-[6-(4-methoxy-benzylcarbamoyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid
4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid methyl ester
4-[6-(4-methoxy-benzylcarbamoyl)-1-methyl-4-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid,
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 3-methoxy-benzylamide
3-(4-methanesulfonyl)-benzyl-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
4-Oxo-3-[4-(pyrrolidine-1-sulfonyl)-benzyl]-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide
4-[6-(3-methoxy-benzylcarbamoyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid,
3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide,
3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 3-methoxy-benzylamide,
and 3-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-pyrido[3,4-d]pyrimidine-6-carboxylic acid 4-methoxy-benzylamide
Further preferred compounds are:
3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide
3-(3,4-Difluoro-benzyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide.
More particularly, the invention relates also to the following compounds of formula (I):
3-(4-fluorobenzyl)-6-(3-phenyl-prop-1-ynyl)-3H-quinazolin-4-one,
methyl 4-[4-oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-benzoate,
4-[4-oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid,
3-(4-fluorobenzyl)-6-(3-phenyl-prop-1-ynyl)-3H-pyrido[3,4-d]pyrimidin-4-one,
methyl 4-[6-(3-phenyl-prop-1-ynyl)-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl]-benzoate,
4-[6-(3-phenyl-prop-1-ynyl)-4-oxo-4H-pyrido[3,4-d]pyrimidin-3-ylmethyl]-benzoic acid,
4-[4-oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazoline-3-ylmethyl]-benzoic acid,
4-{6-[3-(4-methoxy-phenyl)-prop-1-ynyl]-4-oxo-4H-quinazoline-3-ylmethyl}-benzoic acid,
4-[4-oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazoline-3-ylmethyl]-benzamide
and 3-[(3,5-difluoro-4-hydroxy)-benzyl]-6-(3-phenyl-prop-1-ynyl)-3H-quinazolin-4-one.
Further preferred compounds are:
4-[6-(3-Imidazol-1-yl-prop-1-ynyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid
4-[4-Oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-benzenesulfonamide
4-[4-Oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-benzonitrile
3-(3-Chloro-benzyl)-6-(4-phenyl-but-1-ynyl)-3H-quinazolin-4-one
3-(3-Chloro-benzyl)-6-(3-phenyl-prop-1-ynyl)-3H-quinazolin-4-one
4-[4-Oxo-6-(3-pyrazol-1-yl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-benzoic acid
6-(3-Phenyl-prop-1-ynyl)-3-[4-(1H-tetrazol-5-yl)-benzyl]-3H-quinazolin-4-one
3-(3,4-Difluoro-benzyl)-6-[3-(pyridin-4-yloxy)-prop-1-ynyl]-3H-quinazolin-4-one
3-(3,4-Difluoro-benzyl)-6-[3-(4-methoxy-phenyl)-prop-1-ynyl]-3H-quinazolin-4-one
N-{4-[4-Oxo-6-(3-phenyl-prop-1-ynyl)-4H-quinazolin-3-ylmethyl]-phenyl}-acetamide
3-(3,4-Difluoro-benzyl)-6-(3-phenyl-prop-1-ynyl)-3H-quinazolin-4-one
3-(4-Acetyl-benzyl)-6-[3-(4-methoxy-phenyl)-prop-1-ynyl]-3H-quinazolin-4-one
6-(3-Phenyl-prop-1-ynyl)-3-pyridin-4-ylmethyl-3H-quinazolin-4-one
6-[3-(4-Methoxy-phenyl)-prop-1-ynyl]-3-pyridin-4-ylmethyl-3H-quinazolin-4-one
Most preferred are the compounds listed in the table below, which refers to the examples later in the application.
The optical isomers, the N-oxides, as well as the addition salts with a pharmaceutically-acceptable acid or base, of the preferred compounds form an integral part of the invention.
The invention also relates to a pharmaceutical composition comprising as active ingredient an effective amount of a compound of formula (I) together with one or more pharmaceutically-acceptable excipients or carriers.
Another embodiment of the invention concerns the use of the compound of formula (I) for the preparation of a medicinal product intended for treating a disease involving therapy by inhibition of matrix metalloprotease, and more particularly of type-13 matrix metalloprotease.
The invention also relates to a method for treating a living body afflicted with a disease involving a therapy by inhibition of matrix metalloprotease, and more particularly of type-13 matrix metalloprotease, the said method comprising the administration of an effective amount of a compound of formula (I) to a patient in need thereof.
A preferred method of treatment according to this invention is treatment of a disease selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary diseases, age-related degeneration and cancers.
More particularly, a preferred method of treatment according to this invention is treatment of disease selected from arthritis, osteoarthritis and rheumatoid arthritis.
The compounds provided by this invention are those defined in formula (I). In formula (I), it is understood that:
a (C1-C6)alkyl group denotes a linear or branched group containing from 1 to 6 carbon atoms; example of such groups, without implying any limitation are methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, hexyl,
a (C2-C6)alkenyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more double bonds; examples of such groups without implying any limitation are vinyl, allyl, 3-buten-1-yl, 2-methyl-buten-1-yl, hexenyl,
a (C2-C6)alkynyl group denotes a linear or branched group containing from 2 to 6 carbon atoms, and one or more triple bonds; examples of such groups without implying any limitation are ethynyl, propynyl, 3-butyn-1-yl, 2-methyl-butyn-1-yl, hexynyl,
a (C1-C6)alkoxy group means the alkyl group as mentioned above bound through an oxygen atom; examples of such compounds without implying any limitation are methoxy, ethoxy, n-propyloxy, tert-butyloxy,
a mono(C1-C6)alkylamino denotes a amino group substituted by one (C1-C6)alkyl group as defined hereinbefore; example of such groups, without implying any limitation are methyl amino, isobutyl amino, ethylamino,
a di(C1-C6)alkylamino denotes a amino group substituted by two (C1-C6)alkyl groups as defined hereinbefore, each alkyl group being identical or different; example of such groups, without implying any limitation are dimethylamino, diethylamino,
an aryl group denotes an aromatic monocyclic or bicyclic system containing from 5 to 10 carbon atoms, and in the case of a bicyclic system, one of the ring of which is aromatic in character, and the other ring of which may be aromatic or partially hydrogenated; examples of such groups without implying any limitation are, phenyl, naphthyl, indenyl, benzocyclobutenyl,
a heteroaryl group denotes an aryl group as described above in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen; examples of such groups without implying any limitation are furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxinyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,5]oxadiazolyl,
a cycloalkyl group denotes a monocyclic or bicyclic system containing from 3 to 10 carbon atoms, this system being saturated or partially unsaturated but without aromatic character; examples of such groups without implying any limitation are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, adamantyl, decalinyl, norbornyl,
a heterocycloalkyl group denotes a cycloalkyl group as defined hereinbefore in which 1 to 4 carbon atoms are replaced by 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen,
a bicycle denotes two fused-monocycle and,
a trihalogeno(C1-C6)alkyl group denotes an alkyl group as defined above which contains a trihalogeno group; examples of such groups without implying any limitation are trifluoromethyl, 2,2,2-trifluoroethyl,
a (C1-C7)acyl group denotes an alkyl group or a aryl group as defined above bound through a carbonyl group; examples of such groups without implying any limitation are acetyl, ethylcarbonyl, benzoyl,
a multiple bond denotes double bond or triple bond,
a halogen atom means fluoro, chloro, bromo or iodo,
optical isomers refer to racemates, enantiomers and diastereoisomers.
The invention also relates to the pharmaceutically acceptable salts of the compounds of formula (I). A review of the pharmaceutically acceptable salts will be found in J. Pharm. Sci., 1977, 66, 1-19.
Pharmaceutically acceptable acids mean non-toxic salts derived from mineral or organic acids. Among those there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, citric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, benzoic acid, toluenesulfonic acid, etc . . .
Pharmaceutically acceptable bases mean non-toxic salts derived from mineral or organic bases. Among those, there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, tert-butylamine, dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, quaternary ammonium hydroxides etc . . .
A living body is a mammal, including a human, dog, cat, cow, horse, pig, monkey, rat, mouse, sheep, guinea pig, rabbit, and chimpanzee. Preferred living body is a human.
A preferred method of treating cancer is treating breast cancer. More preferred is treating human breast cancer.
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (II): 
in which X1, X2, X3, and Y1 have the same definitions as the compound of formula (I), and T represents a group (C1-C6)alkyl,
compound of formula (II) which is treated with a compound of formula (III): 
in which Z1, Y2, R2, A, n and m have the same definitions as the compound of formula (I),
by activating the acid function with an activator, in the presence of diisopropylethylamine and a solvent, to yield the compound of formula (IV): 
in which X1, X2, X3, Y1, T, Z1, Y2, R2, A, n and m are as defined hereinbefore,
compound of formula (IV) in which the ester group is hydrolyzed and the subsequently compound obtained is then treated with an activator in the presence of a base and a primary amine with the general formula R1xe2x80x94NH2 in which R1 is as defined in the compound of formula (I),
to yield the compound of formula (V): 
in which X1, X2, X3, Y1, Y2, Z1, R2, R1, A, n and m are as defined hereinbefore, which compound of formula (V) is treated:
either with triethyl orthoformate under heating condition, to yield the compound of formula (I/a), which is a particular case of the compound of formula (I): 
in which X1, X2, X3, Y1, Y2, Z1, R2, R1, A, n and m are as defined hereinbefore,
or under heating condition in the presence of acid, with a compound of formula (VI): 
in which R4 has the same definition as the compound of formula (I),
to yield the compound of formula (I/b), which is a particular case of the compound of formula (I): 
in which X1, X2, X3, Y1, Y2, Z1, R2, R1, R4, A, n and m are as defined hereinbefore,
or with a compound of formula (VII) in basic condition: 
in which R4 and R5 have the same definition as the compound of formula (I),
to yield the compound of formula (I/c), which is a particular case of the compound of formula (I): 
in which X1, X2, X3, Y1, Y2, Z1, R2, R1, R4, R5, A, n and m are as defined hereinbefore,
which compound of formula (I/c) is optionally treated with a hydride, in the presence of a compound of formula (VIII):
R6xe2x80x94Halxe2x80x83xe2x80x83(VIII)
in which R6 has the same definition as the compound of formula (I), to yield the compound of formula (l/d), which is a particular case of the compound of formula (I): 
in which X1, X2, X3, Y1, Y2, Z1, R2, R1, R4, R5, R6, A, n and m are as defined hereinbefore,
compounds of formulae (I/a), (I/b), (I/c) and (I/d) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (X): 
in which X1, X2, and X3 have the same definitions as the compound of formula (I), and Hal represents a halogen atom,
which compound of formula (X) is treated in a first step with a derivate of phosgene to yield the compound of formula (XI): 
in which X1, X2, X3 and Hal are as defined hereinbefore,
which compound of formula (XI) is treated in basic medium with a primary amine of general formula R1xe2x80x94NH2 in which R1 has the same definition as in the compound of formula (I),
to yield the compound of formula (XII): 
in which X1, X2, X3, R1 and Hal are as defined hereinbefore,
which compound of formula (XII) is treated:
either with triethyl orthoformate under heating condition, to yield the compound of formula (XIII/a): 
in which X1, X2, X3, R1 and Hal are as defined hereinbefore,
or under heating condition in the presence of an acid, with a compound of formula (VI): 
in which R4 has the same definition as the compound of formula (I),
to yield the compound of formula (XIII/b): 
in which X1, X2, X3, Hal, R1 and R4 are as defined hereinbefore,
or with a compound of formula (VII) in basic conditions: 
in which R4 and R5 have the same definition as the compound of formula (I),
to yield the compound of formula (XIII/c): 
in which X1, X2, X3, Hal, R1, R4 and R5 are as defined hereinbefore,
which compound of formula (XIII/c) is optionally treated with a hydride, in the presence of a compound of formula (VIII):
R6xe2x80x94Halxe2x80x83xe2x80x83(VIII)
in which R6 has the same definition as the compound of formula (I), and Hal is a halogen atom,
to yield the compound of formula (XIII/d), which is a particular case of the compound of formula (I): 
in which X1, X2, X3, Hal, R1, R4, R5 and R6 are as defined hereinbefore,
all compounds of formulae (XIII/a), (XIII/b), (XIII/c) and (XIII/d) constitute the compound of formula (XIII/e): 
in which X1, X2, X3, Hal, R1 and G1 are as defined in the compound of formula (I),
compound of formula (XIII/e) which is treated under conditions of palladium-catalyzed alkynylation with a compound of formula (XIV): 
in which Z1, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (I/e), which is a particular case of the compound of formula (I): 
in which X1, X2, X3, R1, G1, Z1, R2, A, n and m have the same definitions as the compound of formula (I),
compounds of formula (I/e) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
An alternative way to obtain the compound of formula (XIII/a) from compound of formula (XI) is described in the following scheme 1: 
Wherein X1, X2, X3, R1 and Hal, are as defined above.
In a first step, compound of formula (XI) is treated with an aqueous solution of ammonium hydroxide to yield compound of formula (XI/a) which is reacted with triethyl orthoformate in the presence of a catalytic amount of acid like para-toluene sulfonic acid (PTSA). The 3H-quinazolin-4-one (XI/b) obtained is condensed in basic medium to a compound of formula R1xe2x80x94Hal, in which R1 is as defined in the compound of formula (I) and Hal represents a halogen, to yield the compound of formula (XIII/a).
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIII/e): 
in which X1, X2, X3, R1 and G1 are as defined in the compound of formula (I), and Hal is a halogen atom,
compound of formula (XIII/e) which is condensed, in the presence of dichlorobis(triphenylphosphine)palladium, cupper iodide and N,Nxe2x80x2-diisopropylethylamine in dimethylformamide, on a compound of formula (XV): 
in which Z1, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (I/e), which is a particular case of the compound of formula (I): 
in which X1, X2, X3, R1, G1, Z1, R2, A, n and m have the same definitions as the compound of formula (I).
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIII/e): 
in which X1, X2, X3, R1 and G1 are as defined in the compound of formula (I), and Hal, is a halogen atom,
compound of formula (XIII/e) which is reacted with carbon monoxide in an alkaline medium in the presence of a protic solvent like methanol and a catalytic amount of palladium, to yield the compound of formula (XVI): 
in which X1, X2, X3, R1 and G1 are as defined in the compound of formula (I),
compound of formula (XVI) which is hydrolysed under basic medium to yield the compound of formula (XVII): 
in which X1, X2, X3, R1 and G1 are as defined in the compound of formula (I),
compound of formula (XVII) which is condensed under basic medium in the presence of a Mukayama reagent, on the compound of formula (XVIII): 
in which Z1, R2, A, n and m have the same definitions as the compound of formula (I),
to yield the compound of formula (I/f), which is a particular case of the compound of formula (I): 
in which X1, X2, X3, Z1, R2, R1, A, n and m are as defined hereinbefore,
compounds of formula (I/f) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
The invention also relates to a process for the preparation of compounds of formula (I), which uses as starting material a compound of formula (XIX): 
in which Hal represents a halogen atom,
compound of formula (XIX) which is heated in the presence of formamidine acetate in a polar solvent like 2-methoxyethan-1-ol, to yield the compound of formula (XX): 
in which Hal is as defined hereinbefore,
compound of formula (XX) which is treated in basic medium with a compound of formula R1xe2x80x94Hal, in which R1 is as defined in the compound of formula (I) and Hal represents a halogen atom, to yield the compound of formula (XXI): 
in which Hal and R1 are as defined hereinbefore,
compound of formula (XXI) which is reacted with carbon monoxide under basic medium in the presence of an alcoholic solvent like methanol and a catalytic amount of palladium like PdCl2(dppf), to yield the compound of formula (XXII): 
in which R1 is as defined hereinbefore,
compound of formula (XXII) which is condensed, in the presence of trimethylaluminium, with a compound of formula (XVIII): 
in which Z1, R2, A, n and in have the same definitions as the compound of formula (I),
to yield the compound of formula (I/g), which is a particular case of the compound of formula (I): 
in which Z1, R2, R1, A, n and m are as defined hereinbefore,
compounds of formula (I/g) constitute some compounds of the invention, which are purified, where appropriate, according to a conventional purification technique, which are separated, where appropriate, into their different isomers according to a conventional separation technique, and which are converted, where appropriate, into addition salts thereof with a pharmaceutically-acceptable acid or base, or into N-oxide thereof.
The compounds of the invention that are present in the form of a mixture of diastereoisomers are isolated in a pure form by using conventional separation techniques such as chromatography.
As mentioned above, compounds of formula (I) of the present invention are matrix metalloprotease inhibitors, and more particularly inhibitors of the enzyme MMP-13.
In this respect, their use is recommended for the treatment of diseases or complaints involving a therapy by MMP-13 inhibition. By way of example, the use of the compounds of the present invention may be recommended for the treatment of any pathology in which destruction of extracellular matrix tissue occurs, and most particularly pathologies such as arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration and cancers.
The present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an isomer thereof, a N-oxide thereof, or an addition salt thereof with a pharmaceutically-acceptable acid or base, alone or in combination with one or more pharmaceutically-acceptable, inert, non-toxic excipients or carriers.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, intravaginal, rectal, nasal, perlingual, buccal, ocular or respiratory administration.
Pharmaceutical compositions according to the invention for parenteral injections especially include aqueous and non-aqueous sterile solutions, dispersions, suspension and emulsions, and also sterile powders for reconstituting injectable solutions or dispersions.
Pharmaceutical compositions according to the invention for oral administration in solid form especially include tablets or dragees, sublingual tablets, sachets, gelatin capsules and granules, for oral, nasal, buccal or ocular administration in liquid form, especially include emulsions, solutions, suspensions, drop, syrups and aerosols.
Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and those for per- or trans-cutaneous administration especially include powders, aerosols, creams, ointment, gels and patches.
The pharmaceutical compositions mentioned hereinbefore illustrate the invention but do not limit it in any way.
Among the pharmaceutically acceptable, inert, non-toxic excipients or carriers there may be mentioned, by way of non-limiting example, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, swelling agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, colourants, aromatizing agents etc . . .
The useful dosage varies according to the age and weight of the patient, the administration route, the pharmaceutical composition used, the nature and severity of the disorder and the administration of any associated treatments. The dosage ranges from 2 mg to 1 g per day in one or more administrations. The compositions are prepared by methods that are common to those skilled in the art and generally comprise 0.5% to 60% by weight of active principle (compound of formula (I)) and 40% to 99.5% by weight of pharmaceutically acceptable excipients or carriers.
The examples that follow illustrate the invention but do not limit it in any way.
The starting materials used are products that are known or that are prepared according to known operating procedures. The various preparations yield synthetic intermediates that are useful in preparation of the compounds of the invention. Some of these intermediates are new compounds.
The structures of the compounds described in the Examples and Preparations were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, . . . )
In the Preparations and Examples, it is understood that:
DMF means Dimethylformamide,
THF means tetrahydrofurane,
DMSO means dimethylsulfoxide,
TOTU means O-(ethoxycarbonyl)cyanomethylamino)N-N-Nxe2x80x2-Nxe2x80x2-tetramethyl uronium fluoroborate,
DIPEA means diisopropylethylamine.